SUMMARY?PROJECT 4: MEMORY FUNCTION AND COGNITION DECLINE. Despite considerable advances in imaging and biomarkers, we still lack a complete understanding of the link between the molecular pathology of Alzheimer's disease (AD) and the emergence of the earliest clinical manifestations. It remains extremely challenging to disambiguate the earliest memory changes that predict whether an individual will progress toward symptomatic stages of AD from the memory alterations thought to occur over the course of ?normal? brain aging. Over the first funding cycle of the Harvard Aging Brain Study (HABS), we found that the 30% of clinically normal (CN) older individuals who show elevated amyloid-beta (A?) accumulation on PET imaging: 1) perform slightly worse on cross-sectional neuropsychological tests, specifically on episodic memory; 2) demonstrate impaired ability to modulate functional MRI activity during memory paradigms; 3) are more likely to report subjective memory concerns; and 4) demonstrate decreased practice effects on repeated testing. However, our findings suggest that markers of A? accumulation in isolation are not sufficient to predict imminent cognitive decline, and that we will need a combination of A? and neurodegeneration (ND) markers to more accurately predict the emergence of clinical symptoms. Over the next cycle, we will add a new PET ligand that binds to tau aggregates (T807 Tau PET), in combination with PiB-PET amyloid imaging, to investigate the impact of A? and Tau on cognitive performance and the networks supporting memory function. In Aim 1, we will optimize sensitive measures to detect early cognitive alterations related to A? and Tau. In addition to the comprehensive annual neuropsychological battery, we will employ monthly home iPad testing to determine if lack of practice effects over shorter time intervals will prove to be a sensitive indicator of impending cognitive decline. In Aim 2, we will investigate the brain networks supporting memory function with a new fMRI paradigm that juxtaposes retrieval of well-known famous face-name associations with encoding of novel non-famous faces. We will test the hypothesis that Tau is associated with impaired ability to modulate activity in medial temporal lobe memory systems, whereas A? will be related primarily to alterations in the neocortical nodes of the default network. Furthermore, we hypothesize that the ?Tip of the Tongue? phenomenon is not an early indicator of AD-specific synaptic dysfunction, and instead, will be related to white matter changes. In Aim 3, we will investigate the relationship of multiple imaging markers to longitudinal cognitive decline, both retrospectively and prospectively, to test the hypothesis that accumulation of both A? and Tau are required for cognitive decline along the trajectory of preclinical AD. We will also explore the proxies of brain and cognitive reserve that may confer resilience to pathology. Project 4 will leverage the rich longitudinal cognitive and imaging data available on the HABS cohort, integrating closely with Cores and other Projects to elucidate the impact of A? and Tau on cognition and memory network function in the aging brain.